Zofenopril is a non-peptidic orally active sulphydryl ACE inhibitor with long lasting action, which is approved for the treatment of hypertension.
U.S. Pat. No. 6,515,012 and U.S. Pat. No. 6,521,760 discuss the prior art disclosed in U.S. Pat. No. 4,316,906 and describe the method for the preparation of zofenopril calcium as disclosed in U.S. Pat. No. 4,316,906 as comprising the following steps: condensation between cis-4-(phenylthio)-L-proline and D-3-(benzoylthio)-2-methylpropionyl chloride in aqueous solution keeping the pH at values of 8-8.5 by addition of 5N sodium hydroxide, subsequent acidification with HCl, extraction with isobutyl acetate and concentration of the extracts, washing with saline solution, to give (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropinoyl]-4-(phenylthio)-L-proline; treatment of the resinous material from the previous step in isopropanol solution with potassium 2-ethyl-hexanoate to obtain the corresponding potassium salt; dissolution of the potassium salt in water to a 5% concentration and very slow addition, with simultaneous seeding, of a slight excess of a 2N calcium chloride aqueous solution to precipitate the desired calcium salt, washing the resulting product thoroughly with water, drying under vacuum at a comparatively high temperature to give the desired calcium salt as dry powder with a melting point of about 250° C.; alternatively (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropinoyl]-4-(phenylthio)-L-proline is dissolved in ethanol and treated with the same volume of an aqueous suspension containing one equivalent of CaO; after removing ethanol and subsequently washing with ether, the aqueous suspension is freeze-dried to obtain the calcium salt with a melting point of 235-237° C.
According to U.S. Pat. No. 6,515,012 and U.S. Pat. No. 6,521,760, the synthesis described in U.S. Pat. No. 4,316,906 (cited above at points a, b and c) mainly yields polymorph A, but also polymorph B in very variable percentages and never below 20%. Moreover, the alternative synthesis described (cited at point d) affords a partially amorphous product with very variable characteristics, in which polymorph A, when present, is in concentrations much lower than those obtained in the preceding process.
U.S. Pat. No. 6,515,012 and U.S. Pat. No. 6,521,760 both disclose a process for the preparation of substantially pure polymorph A of zofenopril calcium comprising the following steps:
reaction of (S)(−)-3-(benzoylthio)-2-methyl-propanoic acid chloride and cis-4-(phenylthio)-L-proline in water at a pH ranging from 9.0-9.5 and recovery of zofenopril in the acidic form,
salification of acid zofenopril with a potassium salt in alcoholic solution and recovery of the resulting potassium salt,
conversion of the potassium salt to calcium by addition of an aqueous solution of zofenopril potassium salt to a calcium chloride aqueous solution at 70-90° C. with simultaneous seeding to promote the precipitation of polymorph A.
The synthesis disclosed in the aforesaid US patents for the preparation of polymorph A has the following drawbacks:
The reaction is carried out at a relatively high temperature (80-85° C.) at which inter-conversion of the polymorphs is possible.
Substantially pure polymorph A can be obtained from the above process, but the possibility of traces of polymorph B cannot be ruled out.
The aforesaid US patents also disclose a process for the preparation of polymorph B comprising the following steps:
A solution of zofenopril potassium salt (0.27M) is sprayed in lukewarm water (55° C.), while adding a calcium chloride solution, the solution being such that the total amounts of drug and calcium chloride are equimolar.
The resulting suspension containing the slurry product is heated at 85° C. for 12-14 hours to obtain complete conversion to polymorph B.
After cooling at about 25° C., the product is filtered, washed with water until it is substantially free from chloride ions, and then dried under vacuum.
Both, polymorph A and polymorph B, are anhydrous forms of zofenopril calcium.
The present inventors have developed a process for the preparation of a novel crystalline form of zofenopril calcium, which yields a new crystalline form of zofenopril at relatively milder temperature conditions, thereby preventing the inter-conversion of polymorphs. The novel zofenopril calcium polymorph is called polymorph C and it is a monohydrate form of zofenopril calcium.
The novel crystalline form of zofenopril calcium of the present invention can be used in different dosage forms such as tablets, capsules etc.